Acute kidney injury (AKI) is a complex syndrome which affects a significant proportion of hospitalized children. The breadth and impact of AKI on health outcomes in both adults and children have come to the fore in recent years with increasing awareness encouraging research advancement. Despite this, management strategies for most types of AKI remain heavily reliant on fluid and electrolyte management, hemodynamic optimization, nephrotoxin avoidance and appropriate initiation of kidney replacement therapy. Specific drugs targeting the mechanisms involved in AKI remain elusive. Recent improvement in appreciation of the complexity of AKI pathophysiology has allowed for greater opportunity to consider novel therapeutic agents. A number of drugs specifically targeting AKI are in various stages of development. This review will consider some novel and repurposed agents; interrogate the plausibility of the proposed mechanisms of action, as they relate to what we know about the pathophysiology of AKI; and review the level of existing literature supporting their efficacy. The evidence base, particularly in children, is limited.